The provision of proteins which are underexpressed in biological systems using pharmaceutical agents is a promising method of treating or potentially treating a multitude of disease states. The medical and pharmaceutical community has approached the treatment of this type of disease modality by multiple mechanistic and avenues. In one approach, a natural antisense transcript (NAT) of the mRNA corresponding to a particular target protein has been selected as the target. Oligonucleotides and/or modified oligonucleotides have been designed to target the NAT and “up-regulate” the expression of the target mRNA and protein. Because of the vast number of disease states and conditions which require or need new and/or first line pharmaceutical treatment, there is a significant need for new approaches and drugs to modulate protein expression or underexpression.
The prior art in general includes gene therapy, antisense technology, siRNA technology as well as the use of small molecules to regulate protein expression. Most of the antisense technology and the siRNA technology and related patents or patent applications relates to the use of such “drugs” to mitigate (down regulate) the expression of proteins. The therapeutic target is often the mRNA or DNA coding for the particular protein or coding for the RNA which is translated into the protein of interest. Examples of various disclosures from the patent literature are provided below.
U.S. Pat. No. 5,739,119 claims antisense oligonucleotides specific for the muscarinic type 2 acetylcholine receptor mRNA. Administration results in an increase in memory and learning.
U.S. Pat. No. 5,985,663 claims antisense inhibition of interleukin-15 expression.
U.S. Pat. No. 6,165,712 claims molecules which transcriptionally modulate the expression of a gene and increase production of recombinant proteins. This reference discloses the upregulation of proteins. The modulating molecule may comprise an antisense nucleic acid. The modulating molecule may bind to a promoter region upstream of the coding sequence encoding an oncogene or tumor suppressor gene.
U.S. Pat. No. 6,165,990 claims the use of expression vectors which code for antisense nucleotides that target mRNA associated with colon cancer-Gastrin gene.
U.S. Pat. No. 6,303,374 claims antisense modulation of Caspase 3 expression. The antisense nucleotides target nucleic acids encoding caspase 3 for the treatment of Alzheimer's, Parkinson's. ALS, etc.
U.S. Pat. No. 6,376,541 claims a method of treating glaucoma by “upregulating” the production of prostaglandins by treating a patient with an agent that causes the upregulation of the prostaglandin—the agents include interleukin-1, transforming growth factor-beta 1, transforming growth factor-beta 2, platelet derived growth factor, levamisole etc. This patent discloses an example of the use of a drug to upregulate the expression of a small molecule instead of a protein.
U.S. Pat. No. 6,444,464 discloses antisense nucleotides targeted to nucleic acids encoding transcription factors E2F.
U.S. Pat. No. 6,617,122 claims polypeptides, nucleic acid molecules expressing such polypeptides, and a method of treating a human having low HDL comprising administering to such human an ABC1 polypeptide, or cholesterol regulating fragment thereof. The ABC-1 polypeptide is wild type ABC-1 or has a mutation that increases its stability or its biological activity. The patent also discloses candidate compounds that modulate (increase) the level of expression of said protein. Antisense nucleotides to the cDNA of the ABC-1 protein were disclosed. The reference discloses that using a compound to inhibit a transcription factor that represses ABC1 would be expected to result in upregulation of ABC1 and, therefore, raise HDL levels. The transcription factor is a protein.
U.S. Pat. No. 6,710,174 discloses antisense inhibition of vascular endothelial growth factor.
U.S. Pat. No. 7,144,999 discloses oligonucleotides that target hypoxia-inducible factor 1 alpha (aHIF) expression and methods for treating diseases associated with the expression of such a protein. This patent discloses the overexpression of a natural antisense transcript of aHIF that is complementary to the 3′ untranslated region of HIF-1 alpha and which is associated with a human disease (non-pappilary clear-cell renal carcinoma).
U.S. Pat. No. 7,148,204 discloses antisense modulators of BCL-X expression. Modulation induces apoptosis.
U.S. Pat. No. 7,199,107 discloses antisense modulators of Kinesin-like 1 expression.
U.S. Pat. No. 7,202,357 discloses antisense compounds, compositions and methods are disclosed for modulating the expression of acyl CoA cholesterol acyltransferase-2. The compounds are antisense oligonucleotides targeted to nucleic acids encoding acyl CoA cholesterol acyltransferase-2.
U.S. Pat. No. 7,229,976 discloses antisense oligomers targeted to a nucleic acid encoding forkhead box O1A to modulate expression thereof.
U.S. Pat. No. 7,235,534 discloses antisense oligonucleotides that target the genes and mRNAs encoding mammalian estrogen receptors (ER) alpha and/or beta and modulate the receptors' responses. The treatment improves plaque stabilization and vascular healing and endothelial recovery after vascular injury.
U.S. Pat. No. 7,285,288 discloses oligonucleotides that hybridize to Bcl-2 nucleic acids, the gene products are known to interact with the tumorigenic protein Bcl-2.
U.S. Pat. No. 7,335,764 discloses antisense modulators of acyl coA cholesterol acyltransferase-2 expression.
U.S. Pat. No. 7,402,574 discloses antisense compositions and methods for treating cancer. The antisense composition comprises a substantially uncharged antisense compound having a nuclease-resistant backbone, capable of uptake by target cancer cells in the subject, containing between 10-40 nucleotide bases and having a base sequence effective to hybridize to a region of processed or preprocessed human SNAIL RNA transcript having a specific sequence ID NO: 21.
U.S. Pat. No. 7,420,050 discloses antisense molecules which inhibit the expression of TGF-beta. Kidney disease.
U.S. Pat. No. 7,425,545 discloses modulation of C-reactive Protein expression.
U.S. Pat. No. 7,456,154 discloses antisense oligonucleotides against human acetylcholinesterase and uses thereof.
U.S. Pat. No. 7,598,227 discloses modulation of apolipoprotein C-III expression.
U.S. Pat. No. 7,662,948 discloses antisense oligonucleotides against VR1 (capsaicin receptor) for the treatment of pain.
U.S. Pat. No. 7,674,895 discloses siRNAs specific for the VEGF and VEGF receptor genes.
U.S. Pat. No. 7,687,617 discloses oligonucleotides with alternating segments of locked and non-locked nucleotides.
U.S. Pat. No. 7,691,995 discloses in vivo production of small interfering RNAs.
U.S. Pat. No. 7,709,546 discloses modulation of gene expression by oligomers targeted to chromosomal DNA.
U.S. Pat. No. 7,709,630 discloses antisense modulation of connective tissue growth factor expression.
U.S. Pat. No. 7,723,508 discloses modulation of apolipoprotein (A) expression.
U.S. Pat. No. 7,732,422 discloses TRPM-2 antisense therapy for the treatment of cancer.
U.S. Pat. No. 7,732,590 discloses modulation of diacylglycerol acyltransferase 2 expression.
U.S. Pat. No. 7,737,265 discloses RNAi modulation of HIF-1 and therapeutic uses thereof.
U.S. Pat. No. 7,741,305 discloses modulation of apo A1 expression.
US2003/0191075 discloses methods of targeting gene therapy (antisense nucleotides) to specific organs using modified oligonucleotides-lipophilc oligonucleotide conjugates.
US2004/0033480 discloses the use of resveratrol (3,5,4′-trihydroxy-trans-stilbene) to upregulate the expression of apolipoprotein A1.
US2004/0137423 discloses compositions and methods for identifying agents that modulate HDL levels in animals by increasing ABCA1-gene expression.
US2004/0175803 discloses an interferon-alpha induced (upregulated) gene.
The present inventors have discovered new uses of known small molecules that result in the modulation of expression of the SCNA gene family and variants thereof.